Various types of analytical tests related to patient diagnosis and therapy can be performed by analysis of a liquid sample taken from a patient's infections, bodily fluids or abscesses. These assays are typically conducted with automated clinical analyzers onto which tubes or vials containing patient samples have been loaded. The analyzer extracts liquid sample from the vial and combines the sample with various reagents in special reaction cuvettes or tubes. Usually the sample-reagent solution is incubated or otherwise processed before being analyzed. Analytical measurements are often performed using a beam of interrogating radiation interacting with the sample-reagent combination, for example turbidimetric, fluorometric, absorption readings or the like. The measurements allow determination of end-point or rate values from which an amount of analyte related to the health of the patient may be determined using well-known calibration techniques.
A clinical analyzers employs many different processes to identify analytes and throughout these processes, patient liquid samples, and samples in combination with various other liquids like reagents or diluents or re-hydrated compositions, are frequently required to be mixed to a high degree of uniformity. Due to increasing pressures on clinical laboratories to increase analytical sensitivity, there continues to be a need for improvements in the overall processing accuracy of clinical analyzers, even with a trend to employ smaller and smaller patient samples. In particular, liquid sample handling needs to be more accurate in terms of providing a small but well known volume of liquid sample for analysis, producing a need for a sampling technique having a high degree of uniformity, without unduly increasing analyzer cost or requiring a disproportional amount of space. The sampling system vagaries that arise from uncontrolled variations in pumping tube lengths, pumping piston displacements, vacuum levels within closed sample tubes, electromechanical vibrations, and the like, can cause analysis inaccuracies in particular in the instance that small samples, in the range of one microliter, are being aspirated and subsequently analyzed.
Various methods have historically been implemented to provide uniform and known small sample liquids. U.S. Pat. No. 6,589,791 discloses a state-variable feedback control system for controlling the operation of a microfluidic aspirate dispense-system using measurements from one or more pressure sensors to derive information for active feedback control in order to dispense liquid drops of different sizes.
U.S. Pat. No. 6,203,759 discloses a microvolume liquid handling system, a system reservoir is connected with tubing to a pressure control system for controlling the liquid system pressure in the system reservoir. The system reservoir is coupled to one or more microdispensers through a distribution tube having a branched section for each microdispenser. In this embodiment, each microdispenser is coupled to its own flow sensor and to enable a system controller to respectively measure and control the flow of liquid in the each microdispenser.
U.S. Pat. No. 5,927,547 discloses a low volume liquid handling system with a microdispenser employing a piezoelectric transducer attached to a glass capillary, a positive displacement pump for priming and aspirating liquid into the microdispenser, controlling the pressure of the liquid system, and washing the microdispenser between liquid transfers. A pressure sensor is used to measure the liquid system pressure and produce a corresponding electrical signal.
U.S. Pat. No. 5,916,524 discloses an apparatus for dispensing precise quantities of reagents is disclosed including a positive displacement syringe pump in series with a dispenser, such as an aerosol dispenser or solenoid valve dispenser. The pump is controlled by a stepper motor or the like to provide an incremental quantity or continuous flow of reagent to the dispenser.
U.S. Pat. No. 5,763,278 discloses a device for automated pipetting of small volumes of liquid has a pipetting needle, a diluter having a liquid output with a syringe and a valve, the syringe including a piston and a piston drive.
U.S. Pat. No. 5,743,960 discloses a reagent dispensing apparatus is provided including a positive displacement syringe pump in series with a solenoid valve dispenser.
U.S. Pat. No. 5,558,838 discloses a sample preparation apparatus that uses a pair of valves including a first shear valve and a second vent/aspiration valve to control liquid flow between a sample tube, a reaction tube, the atmosphere, a waste pump, and a diluent pump.
U.S. Pat. No. 5,216,926 discloses an automatic sampling apparatus using fluid driven actuators whose control system provides accurate positioning over its range of motion. The actuators are positioned to aspirate liquid contents held within stoppered sample containers and equilibrate pressure in the sample containers to atmospheric prior to aspiration.
Accordingly, from a study of the different approaches taken in the prior art to the problems encountered with aspirating and dispensing precise and known small amounts of liquid solutions, there is a need for an improved approach to the design of a simplified, space-efficient liquid sample and or sample-reagent mixer. In particular, there is a continuing need for a method for eliminating the unknown variabilities that can exist at the upper and lower end portions of an aspirated liquid slug inside a sampling probe.